The University of Colorado is uniquely positioned to be an active and valuable unit in the Cooperative Reproductive Medicine Network (RMN) of the NICHD. This proposal takes advantage of our extensive experience in clinical protocol development and a highly successful record as effective contributors to many large multicenter trials including the existing RMN since 2000. The geographic and population diversity represented by our location as one of the very few academic reproductive medicine centers in the Rocky Mountain region is an additional important asset that we bring to the RMN. Our concept proposal is entitled Male Obesity Hypothesis for Infertility: Treatment Options. Male obesity reduces fertility regardless of the body mass of the female partner. Observational studies have clearly demonstrated that obese men exhibit a compromise in reproductive hormones and semen parameters. A gap in knowledge exists as no clinical trials have been conducted to address treatments for obesity-related male Infertility. Use of aromatase inhibitors in men leads to improvement of compromised sperm parameters and reproductive hormones but pregnancy data is sparse. The central hypothesis of this proposal is that an abnormal endocrine milieu found in obese infertile men negatively impacts reproductive function and can be reversed with aromatase inhibitors. We seek to conduct a multi-center, randomized, double-blind, placebo-controlled trial of an aromatase inhibitor, letrozole, in infertile obese men. Guide by available observational data, this hypothesis will be tested by pursuing three specific aims: 1) To compare the efficacy of an aromatase inhibitor, letrozole, to placebo for the treatment of subfertility in obese men, using live birth as the primary outcome and clinical pregnancy as the secondary outcome; 2) To determine which prospective parameters characterize response to letrozole; and 3) To determine if dietary lipid intake (assessed by red blood cell membrane fatty acid composition) is associated with success of fertility treatment in obese men. The mechanistic approach aimed at correcting the underlying hormonal imbalance represents a novel therapeutic strategy and we shall attempt to further correlate attributes of the treated males with metabolic outcomes of their offspring.